Proteoglycans (PG) are implicated in the atherosclerotic process through their capacity to bind and retain plasma low density lipoproteins (LDL) within the artery wall. As atherosclerosis progresses, arterial PG, particularly dermatan sulfate (DSPG) increase. Our preliminary data indicate that two distinct DSPG molecules (biglycan and decorin) are present in human aorta. The DSPG type which increases with atherosclerosis and the consequences of the increase are presently unknown. The goal of this proposal is to define the structure, metabolism and function of DSPG in the developing human atherosclerotic plaque. The hypothesis is that progression of atherosclerosis is associated with an alteration of smooth muscle cell metabolism resulting in a modulation in production of DSPG type. The modulation is critical in determining how fast atherosclerosis progresses. Production of arterial smooth muscle cell DSPG can be influenced by environmental factors (e.g. growth factors, presence of macrophages, cholesterol accumulations) as well as the intrinsic genetic potential of the cells. Using a comprehensive approach employing biochemical, histological, immunohistochemical, and electron microscopic techniques, properties of human aortic biglycan and decorin will be related to atherosclerotic changes or aging of the artery wall. Structural studies will include properties of core proteins and glycosaminoglycans (GAG). GAG size, chain substructure and content of iduronic acid will be examined since these properties influence potential binding to LDL. Metabolic studies in organ cultures will determine if increased DSPG results from increased synthesis or decreased turnover. A model system that mimics cell-cell interactions within the atherosclerotic plaque will be used to investigate modulations of DSPG in cultured human arterial smooth muscle cells exposed to macrophage conditioned media. Anticipated results of several studies include a stimulation of biglycan, increased binding capacity and affinity of biglycan to plasma LDL, and subsequent uptake of LDLPG by cultured macrophages, thus explaining a new mechanism whereby lipid loading of macrophages and development of atherosclerosis occurs. The ultimate implications include selective targeting to retard atherosclerosis development.